Deprotection processes

ABSTRACT

Acylmercaptoalkanoylamino lactam esters or acids are converted to the corresponding mercaptoalkanoylamino lactam ester or acid under basic conditions by including an agent which minimizes the amount of disulfides. Suitable agents are bismercaptans, phosphine or phosphite reducing agents, zinc metal powder, and sodium hydrosulfite.

[0001] This application is a division of Ser. No. 09/208,135 filed Dec.9, 1998 which claims priority from application Ser. No. 60/070,573 filedJan. 6, 1998.

BACKGROUND OF THE INVENTION

[0002] Mercaptoalkanoylamino lactams have been disclosed as possessinguseful cardiovascular properties as a result of their activity as dualangiotensin converting enzyme inhibitors and neutralmetalloendopeptidase inhibitors. The lactam can be a moncyclic, fusedbicyclic or fused tricyclic as taught by Karanewsky et al. in U.S. Pat.No. 5,552,397, Karanewsky in U.S. Pat. No. 5,504,080, Robl in U.S. Pat.No. 5,508,272, Robl in U.S. Pat. No. 5,525,723, Robl in U.S. Pat. No.5,362,727, Robl in U.S. Pat. No. 5,587,375, Robl et al. in U.S. Ser. No.443,278 filed May 17, 1995, now U.S. Pat. No. 5,877,313, and EP 744,319,Ryono et al. in U.S. Pat. No. 5,635,504 and Karanewsky et al. in U.S.Pat. No. 5,650,408.

[0003] These references disclose coupling an acylmercaptoalkanoic acidsidechain to the amino lactam ester followed by deprotection bytreatment with sodium hydroxide or lithium hydroxide in aqueous alcoholor tetrahydrofuran followed by treatment with aqueous acid to give thedesired mercaptoalkanoylamino lactam products.

SUMMARY OF THE INVENTION

[0004] This invention is directed to an improvement in the deprotectionprocesses used to convert an acylmercaptoalkanoylamino lactam acid orester of the formula

[0005] to the mercaptoalkanoylamino lactam acid or ester of the formula

[0006] and an improvement in the deprotection process used to convertthe mercaptoalkanoylamino lactam ester of formula I to themercaptoalkanoylamino lactam acid of formula I.

[0007] These deprotection reactions are performed under basicconditions. The mercapto group in the lactam acid or ester of formula Iunder such conditions is susceptible to the formation of disulfides ofthe formula

[0008] Such disulfides are themselves an unwanted impurity in thepharmaceutically active mercaptoalkanoylamino lactam acid products offormula I. Also, the disulfides of formula III can convert to otherundesirable side-products. In particular, when R₁ is other thanhydrogen, the disulfide of formula III can convert to themercaptoalkanoyl lactam of formula I having the undesired chirality atthe optically active carbon in the mercaptoalkanoyl sidechain.

[0009] Similarly, the formation of the disulfide impurity of formula IIIcan occur during recrystallization of the mercaptoalkanoylamino lactamproduct of formula I.

[0010] The improvements of this invention reside in including within theabove deprotection and recrystallization processes an agent thatminimizes the amount of the disulfides of formula III and, in turn,minimizes the formation of the undesired epimer of the pharmaceuticallyactive compound of formula I.

[0011] Preferred agents for this purpose are bismercaptans as well asreducing agents such as phosphines and phosphites, zinc metal powder,and sodium hydrosulfite.

DETAILED DESCRIPTION OF THE INVENTION

[0012] The amino lactam acids and esters X₁ shown above include:

[0013] In the above formulas, the various symbols have the definitionslisted below.

[0014] R₁ and R₂ are independently selected from straight or branchedchain alkyl of 1 to 6 carbons, —(CH₂)_(m)-aryl, —(CH₂)_(m)-substitutedaryl, or —(CH₂)_(m)-heteroaryl.

[0015] m is zero or an integer from 1 to 6.

[0016] n is zero or one.

[0017] R₄ and R₅ are independently selected from hydrogen, alkyl,substituted alkyl, alkenyl, —(CH₂)_(m)-cycloalkyl, —(CH₂)_(m)-aryl,—(CH₂)_(m)-substituted aryl, or —(CH₂)_(m)-heteroaryl, or one of R₄ andR₅ is hydrogen and the other is hydroxy, or R₄ and R₅ taken togetherwith the carbon to which they are attached complete a saturatedcycloalkyl ring of 3 to 7 carbons, or R₄ and R₅ taken together with thecarbon to which they are attached complete a keto substituent.

[0018] R₆, R₈ and R₁₀ are independently selected from hydrogen, alkyl,substituted alkyl, alkenyl, -(CH₂)_(m)-cycloalkyl, —(CH₂)_(m)-aryl,—(CH₂)_(m)-substituted aryl, or —(CH₂)_(m)-heteroaryl.

[0019] R₇, R₉ and R₁₁ are independently selected from hydrogen, alkyl,substituted alkyl, alkenyl, —(CH₂)_(m)-cycloalkyl, —(CH₂)_(m)-aryl,—(CH₂)_(m)-substituted aryl, or —(CH₂)_(m)-heteroaryl or R₆ and R₇ takentogether with the carbon to which they are attached complete a saturatedcycloalkyl ring of 3 to 7 carbons, or R₈ and R₉ taken together with thecarbon to which they are attached complete a saturated cycloalkyl ringof 3 to 7 carbons.

[0020] b is zero or one.

[0021] d is zero or one.

[0022] q is an integer from 1 to 4.

[0023] r is one or two.

[0024] t is an integer from 1 to 3.

[0025] v is one or two.

[0026] w is one or two.

[0027] Y₁ is —CH₂—, —(CH₂)₂—, —(CH₂)₃—, —O—, —S—, —CH₂—O—, or —CH₂—S—.

[0028] Y₂ is —CH₂——S—, or —O—.

[0029] Y₃ is —CH₂—, —(CH₂)₂, —(CH₂)3—, —O—or —CH₂—O—.

[0030] Z is O or two hydrogens.

[0031] R₁₇ is hydrogen, alkyl, substituted alkyl, alkenyl,—(CH₂)_(m)-cycloalkyl, —(CH₂)_(m)-aryl, —(CH₂)_(m)-substituted aryl, or—(CH₂)_(m)-heteroaryl.

[0032] Y₅ is —CH₂—, —S—, or —O—provided that Y₅ is —S—or —O—only when dis one.

[0033] Y₆ is —S—or —O—.

[0034] the dashed line - - - represents an optional double bond betweenthe two carbons.

[0035] represents an aromatic heteroatom containing ring selected from

[0036] Y₇ is —S—or —NH—

[0037] Y₈ is —S—, —O—or —NH—

[0038] R₁₈ and R₁₉ are independently selected from hydrogen, alkyl,—(CH₂)_(m)-aryl, or R₁₈ and R₁₉ together with the carbon and nitrogenatoms to which they are attached complete a five or six membered ring.

[0039] R₁₂ is hydrogen or an acid protecting group such as methyl,ethyl, propyl, phenyl or benzyl.

[0040] The term “alkyl” refers to straight or branched radicals of 1 to7 carbons, preferably 1 to 4 carbons.

[0041] The term “substituted alkyl” refers to such straight or branchedchain radicals of 1 to 7 carbons wherein one, two or three hydrogenshave been replaced by a hydroxy, amino, cyano, Cl, Br, F,trifluoromethyl, —NH(alkyl of 1 to 4 carbons), —N(alkyl of 1 to 4carbons)₂, alkoxy of 1 to 4 carbons, alkylthio of 1 to 4 carbons, orcarboxy. The preferred “substituted alkyl” is of 1 to 4 carbons with onehydrogen replaced by hydroxy, amino, Cl, or Br.

[0042] The term “alkenyl” refers to straight or branched chain radicalsof 3 to 7 carbon atoms having one or two double bonds. Preferred“alkenyl” groups are straight chain radicals of 3 to 5 carbons havingone double bond.

[0043] The term “cycloalkyl” refers to saturated rings of 3 to 7 carbonswith cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl beingpreferred.

[0044] The term “aryl” refers to phenyl, 1-naphthyl and 2-naphthyl withphenyl being preferred.

[0045] The term “substituted aryl” refers to phenyl, 1-naphthyl and2-naphthyl having a substituent selected from alkyl of 1 to 4 carbons,alkoxy of 1 to 4 carbons, alkylthio of 1 to 4 carbons, Cl, Br, F,hydroxy, trifluoromethyl, amino, —NH(alkyl of 1 to 4 carbons), or—N(alkyl of 1 to 4 carbons)₂, di and tri-substituted phenyl, 1-naphthyl,or 2-naphthyl wherein said substituents are selected from methyl,methoxy, Cl, Br, methylthio, hydroxy or amino.

[0046] The term “heteroaryl” refers to unsaturated rings of 5 or 6 atomscontaining one or two O and S atoms and/or one to four N atoms providedthat the total number of hetero atoms in the ring is 4 or less. Theheteroaryl ring is attached by way of an available carbon or nitrogenatom. Preferred heteroaryl groups include 2-, 3-, or 4-pyridyl,4-imidazolyl, 4-thiazolyl, 2- and 3-thienyl and 2- and 3-furyl. The termheteroaryl also includes bicyclic rings wherein the five or six memberedring containing O, S and N atoms as defined above is fused to a benzeneor pyridyl ring. Preferred bicyclic rings are 2- and 3-indolyl and 4-and 5-quinolinyl.

[0047] The acylmercaptoamino lactam esters of formula II are prepared bycoupling the acylmercapto containing sidechain of the formula (XXIV)

[0048] with the amino lactam ester (XXV)

H—X₁.

[0049] The above reaction can be performed in an organic solvent such asmethylene chloride and in the presence of a coupling reagent such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicyclohexylcarbodiimide,benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate,or carbonyldiimidazole. Alternatively, the acylmercapto carboxylic acidof formula XXIV can be converted to an activated form such as an acidchloride, mixed anhydride, symmetrical anhydride, activated ester, etc.,prior to coupling.

[0050] The starting materials of formulas XXIV and XXV and the resultingacylmercaptoalkanoylamino lactam esters of formula II are described inthe prior art. For example, the above compounds wherein X₁ is as definedin formulas IV to XIV are described by Karanewsky et al. in U.S. Pat.No. 5,552,397 whose disclosure is hereby incorporated by reference. Theabove compounds wherein X₁ is as defined in formula XV are described byRobl in U.S. Pat. No. 5,508,272 whose disclosure is hereby incorporatedby reference. The above compounds wherein X₁ is as defined in formulaXVI are described by Karanewsky in U.S. Pat. No. 5,504,080 whosedisclosure is hereby incorporated by reference. The above compoundswherein X₁ is as defined in formula XVII are described by Robl in U.S.Pat. No. 5,525,723 whose disclosure is hereby incorporated by reference.The above compounds wherein X₁ is as defined in formula XVIII aredescribed by Robl in U.S. Pat. No. 5,362,727 whose disclosure is herebyincorporated by reference. The above compounds wherein X₁ is as definedin formula XIX and XX are described by Robl in U.S. Pat. No. 5,587,375whose disclosure is hereby incorporated by reference. The abovecompounds wherein X₁ is as defined in formula XXI are described by Ryonoet al. in U.S. Pat. No. 5,635,504 whose disclosure is herebyincorporated by reference. The above compounds wherein X₁ is as definedin formula XXII are described by Karanewsky et al. in U.S. Pat. No.5,650,408 whose disclosure is hereby incorporated by reference. Theabove compounds wherein X₁ is as defined in formula XXIII are describedby Robl et al. in EP 743,319 and in U.S. Ser. No. 443,278 filed May 17,1995 now U.S. Pat. No. 5,877,313 whose disclosure is hereby incorporatedby reference.

[0051] The deprotection processes of this invention include conversionof the acylmercaptoalkanoylamino lactam acid or ester of formula II tothe mercaptoalkanoylamino lactam of formula I The improvement in thisprocess resides in including in the basic hydrolysis reaction thatremoves the acyl functional group R₂—C(O)— an agent that minimizes theamount of the disulfides of formula III and, in turn, minimizes theformation of the undesired epimer of the pharmaceutically activecompound of formula I.

[0052] When the acylmercaptoalkanoylamino lactam of formula II is acarboxylic acid, i.e. R₁₂ in the definition of X1 in formula II ishydrogen, then the acyl protecting group R₂—C(O)— is removed in a singlestep to give the pharmaceutically active lactam of formula I. Thisdeprotection process involves treating the lactam carboxylic acid offormula II with an alkali metal or alkaline earth metal hydroxide orcarbonate or with an amine in a suitable solvent containing a sufficientamount of an agent that minimizes the amount of the disulfides offormula III. Suitable agents for this purpose include bismercaptans aswell as phosphine and phosphite reducing agents, zinc metal powder, andsodium hydrosulfite. Such agents can be present in an amount from about1 mole to about 20 mole percent, preferably from about 5 mole percent toabout 10 mole percent in the reaction mixture. This deprotectionreaction can be performed at a temperature of from about −20° C. toabout 45° C. Following completion, the reaction is acidified with anaqueous acid such as HCl acetic acid, propanoic acid, sulfuric acid,phosphoric acid, or oxalic acid to precipitate out the pharmaceuticallyactive lactam of formula I.

[0053] Suitable alkali metal and alkaline earth metal hydroxides andcarbonates for this deprotection process include sodium hydroxide,potassium hydroxide, lithium hydroxide, sodium carbonate, potassiumcarbonate, and lithium carbonate. Amines useful in this deprotectionprocess include H₂N-alkyl, H₂N—(CH₂)_(m)-aryl, and hydroxyalkylamineswherein alkyl, aryl, and m are as defined above. Methylamine,ethylamine, benzylamine, and ethanolamine are preferred. Suitablesolvents for this deprotection process include methanol, aqueousmethanol, ethanol, aqueous ethanol, tetrahydrofuran, aqueoustetrahydrofuran, isopropanol, aqueous isopropanol, acetonitrile, aqueousacetonitrile and water.

[0054] When the acylmercaptoalkanoylamino lactam of formula II is acarboxylic acid ester, i.e. R₁₂ in the definition of X₁ in formula II isan acid protecting group such as methyl, ethyl, propyl, phenyl orbenzyl, then the acyl protecting group R₂—C(O)— and the carboxylic acidprotecting group can be removed in a single step or in two steps to givethe pharmaceutically active lactam of formula I. In the single stepdeprotection process, the lactam carboxylic acid ester of formula II istreated under aqueous conditions with an alkali metal or alkaline earthmetal hydroxide or carbonate in a suitable solvent containing asufficient amount of an agent that minimizes the amount of thedisulfides of formula III. Suitable agents for this purpose includebismercaptans as well as phosphine and phosphite reducing agents, zincmetal powder, and sodium hydrosulfite. Such agents can be present in anamount from about 1 mole percent to about 20 mole percent, preferablyfrom about 5 mole percent to about 10 mole percent in the reactionmixture. This deprotection reaction can be performed at a temperature offrom about −20° to about 45° C. Following completion, the reaction isacidified with an aqueous acid such as HCl, acetic acid, propanoic acid,sulfuric acid, phosphoric acid, or oxalic acid to precipitate out thepharmaceutically active lactam of formula I.

[0055] Suitable alkali metal and alkaline earth metal hydroxides andcarbonates for this one step deprotection process are as defined above.Suitable solvents for this one step deprotection process includemethanol, ethanol, isopropanol, acetonitrile, and tetrahydrofuran. Thisreaction is performed under aqueous conditions meaning that water ispresent in the solvent and/or in the reagents.

[0056] The improved deprotection processes of this invention alsoinclude the process in which the acylmercaptoalkanoylamino lactam esterof formula II is converted to the mercaptoalkanoylamino lactam ester offormula I. This process involves removal of the acyl group R₂—C(O)— bytreating the acylmercaptoalkanoylamino lactam ester of formula II withan alkali metal or alkaline earth hydroxide or carbonate or with anamine in a suitable solvent containing a sufficient amount of an agentthat minimizes the amount of the disulfides of formula III and, in turn,minimizes the formation of the undesired epimer of the pharmaceuticallyactive compound of formula I. Suitable agents for this purpose includebismercaptans as well as phosphine and phosphite reducing agents, zincmetal powder, and sodium hydrosulfite. Such agents can be present in anamount from about I mole percent to about 20 mole percent, preferablyfrom about 5 mole percent to about 10 mole percent in the reactionmixture. When an alkali metal or alkaline earth metal hydroxide orcarbonate is employed, the reaction is performed under non-aqueousconditions. When an amine is employed, the reaction is performed underaqueous conditions. This deprotection reaction is performed at atemperature of from about −20° C. to about 45° C. Following completion,the reaction is acidified with an aqueous acid such as HCl, acetic acid,propanoic acid, sulfuric acid, phosphoric acid or oxalic acid toprecipitate out the mercaptoalkanoylamino lactam ester of formula I.

[0057] Suitable alkali metal and alkaline earth metal hydroxides andcarbonates and amines for this first deprotection step are as definedabove. Suitable solvents include methanol, ethanol, isopropanol,acetonitrile, and tetrahydrofuran.

[0058] The improved deprotection processes of this invention alsoinclude the process in which the mercaptoalkanoylamino lactam ester offormula I is converted to the pharmaceutically activemercaptoalkanoylamino lactam of formula I wherein R₁₂ is hydrogen. Thisprocess involves removal of the carboxylic acid protecting group bytreating the lactam ester of formula I with an alkali metal or alkalineearth metal hydroxide or carbonate under aqueous conditions in asuitable solvent containing a sufficient amount of an agent thatminimizes the amount of the disulfide of formula III, and in turn,minimizes the formation of the undesired epimer of the pharmaceuticallyactive compound of formula I. Suitable agents for this purpose includebismercaptans as well as phosphine and phosphite reducing agents, andzinc metal powder. Such agents can be present at from about 1 molepercent to about 20 mole percent, preferably from about 5 mole percentto about 10 mole percent in the reaction mixture. This deprotection isperformed at a temperature of from about −20° C. to about 45° C.Following completion, the reaction is acidified with an aqueous acidsuch as HCl, acetic acid, propanoic acid, sulfuric acid, phosphoricacid, or oxalic acid to precipitate out the pharmaceutically activelactam of formula I.

[0059] Suitable alkali metal and alkaline earth metal hydroxides andcarbonates for this deprotection step are as defined above. Suitablesolvents include water, methanol, ethanol, isopropanol, acetonitrile andtetrahydrofuran.

[0060] In the improved recrystallization and reprocessing process ofthis invention, the mercaptoalkanoylamino lactam product of formula I isadded to a suitable solvent containing a sufficient amount of an agentthat minimizes the amount of the disulfides of formula III, and in turn,minimizes the formation of the undesired epimer of the pharmaceuticallyactive compound of formula I. Suitable agents for this purpose includebismercaptans as well as phosphine and phosphite reducing agents, zincmetal powder, and sodium hydrosulfite. Such agents can be present atfrom about 1 mole percent to about 20 mole percent, preferably fromabout 5 mole percent to about 10 mole percent in the recrystallizationmixture. The resulting slurry is subjected to changes in temperatureand/or pH, optionally filtered, and then subjected to additional changesin temperature and/or pH to effect the recrystallization. For example,the slurry can be heated at from about 25° C. to the reflux temperatureto dissolve the solids, the solution is then filtered, the combinedfiltrates are cooled to about room temperature, and desired product iscollected. Alternatively, the slurry is treated to raise the pH above atleast about 8 by the addition of a basic material such as an alkalimetal or alkaline earth metal hydroxide or carbonate, afterward the pHis lowered to at least below about 8 and preferably below about 6.0 andthe product is precipitated out by the addition of an acid such as HCl,acetic acid, propanoic acid, sulfuric acid, phosphoric acid, or oxalicacid, the product is filtered off, washed with water and tert-butylmethyl ether, and dried in vacuo.

[0061] Suitable solvents for the recrystallization process includemethanol, ethanol, isopropanol and mixtures thereof.

[0062] The bismercaptans employed in the above deprotection andrecrystallization procedure are compounds which in the presence of thedisulfide of formula III will cleave such disulfides by forming a stablering. Suitable bismercaptans are those of the formula (XXVI)

[0063] wherein k is an integer from 1 to 4 and each X₂ is independentlyselected from hydrogen and hydroxy as well as 1,2-benzenedimethanethiol,1,3-butanedithiol meso-α, α′-dimercaptoadipic acid, disodium salt, anddurene-α(1), α(2)-dithiol. Preferred bismercaptans are dithiothreitoland dithioerythritol. Suitable phosphine reducing agents includetributyl phosphine and triphenyl phosphine. Suitable phosphite reducingagents include triethyl phosphite. The preferred reagent for use in thedeprotection and recrystallization reactions of this invention isdithiothreitol.

[0064] By minimizing the amount of the disulfides of formula III in thereaction mixture according to the improved deprotection andrecrystallization processes of this invention, the by-products of thedisulfide of formula III are also minimized. Such by-products include,when R₁ is other than hydrogen, the mercaptoalkanylamino lactams offormula I having the undesired chirality at the optically active carbonin the sidechain.

[0065] In the preferred embodiments of this invention, X₁ in theacylmercaptoalkanoylamino lactam acid or ester of formula II is offormula IV or formula XV, n is zero, R₁ is benzyl, and R₂ is methyl.When X₁ is of formula IV, q is preferably two, R₄, R₅, R₁₀, and R₁₁ arepreferably hydrogen, b is preferably zero, R₁₂ is preferably hydrogen orethyl, and R₆ and R₇ are preferably independently selected from hydrogenand alkyl of 1 to 4 carbons, especially where R₆ and R₇ are both methyl.When X₁ is of formula XV, v is preferably two, d is preferably one, Y₅is preferably —CH₂—, Y₆ is preferably —S—, and R₁₂ is preferablyhydrogen or methyl.

[0066] The asterick (*) in formulas I, II and XXIV represent anasymmetric carbon in the acylmercaptoalkanoyl and mercaptoalkanoylsidechain. In the preferred compounds, this asymmetric center has theabsolute configuration S. As shown in formula IV to XXXIII otherasymmetric centers are present in the various amino lactam rings.

[0067] The pharmaceutically active products of formula I wherein R₁₂ ishydrogen are useful cardiovascular agents particularly useful in thetreatment of hypertension and congestive heart failure. Thepharmaceutically active products can be formulated in amounts effectivefor treating hypertension or congestive heart failure as described byKaranewsky et al. in U.S. Pat. No. 5,552,397, Karanewsky in U.S. Pat.No. s 5,504,080 and 5,650,408, Robl in U.S. Pat. No. s 5,508,272,5,525,723, 5,587,375 and 5,362,727, Robl in U.S. Ser. No. 443,278 filedMay 17, 1995 and EP 743,319 and, Ryono et al. in U.S. Pat. No.5,635,504.

[0068] The following examples are illustrative of the invention.

EXAMPLE 1 [4S- [4α(R*), 7α,10aβ]]-Octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-5-oxo-7H-pyrido[2, 1-b][1,3]thiazepine-7carboxyl acid

[0069][4S-[4α(R*),7α,10aβ]]-Octahydro-4-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylicacid, methyl ester (5.0 g, 10.76 mmole) [prepared as described in any ofExamples 3(c), 11(i), 22(b), 23(i), or 24 of U.S. Pat. No. 5,508,272]was dissolved in methanol (45 ml) in a 250 ml flask equipped with anaddition funnel, internal temperature probe and argon inlet. To thesolution was added DL-dithiothreitol (83 mg, 0.538 mmole). The solutionwas sparged with argon for 15 minutes and then kept under argon. Thesolution was cooled to 0° C. in an ice bath. In the addition funnel, 1Nsodium hydroxide solution (65 ml, 64.57 mmole) was sparged with argonfor 30 minutes. The sparged sodium hydroxide solution was added to thereaction flask over 20 minutes so that the internal temperature did notexceed 5° C. The reaction was allowed to stir at 0° C. for 30 minutes,and then the ice bath was removed to allow the reaction to warm to roomtemperature over one hour. The reaction was stirred at room temperaturefor an additional two hours at which point TLC confirmed that thereaction was complete. A pH probe and a reflux condenser were attachedto the reaction flask. The reaction was acidified with previouslyargon-sparged 3N HCl solution to a pH between 8 and 9. The mixture waswarmed to 40° C. (internal temperature probe) and further acidified withvigorous stirring to pH 2. The resulting slurry was stirred at 40° C.for 30 minutes and then allowed to cool to room temperature for onehour. The product was collected by filtration and washed with distilledwater (80 ml volumes) until the wash-water tested negative for chloridewith silver nitrate solution. The product was washed with additionalwater (2×25 ml) and air-dried for 30 minutes. The product was washedwith t-butyl methyl ether (2×10 ml) and hexane (2×10 ml), air-dried, anddried under high vacuum overnight to give 4.00 g title product (94%yield) as a white crystalline solid; m.p. 205 - 207° (decomp.);[α]_(D)=−68.0° (c=1, dimethylformamide). TLC: R_(f)=0.63 (silica gel, 2%acetic acid/ethyl acetate; visualized by UV light and cericsulphate/ammonium molybdate).

[0070] Anal. calcl'd for C₁₉H₂₄N₂O₄S₂*1.1 H₂O: C, 55.25; H, 5.98; N,6.78; S, 15.52. Found: C, 55.10; H, 5.87; N, 6.74; S, 15.33.

EXAMPLE 2[S-(R*,R*)]-Hexahydro-6-[(2-mercapto-1-oxo-3-3phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid

[0071][S-(R*,R*)]-Hexahydro-6-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid, ethyl ester (2.0 g, 4.46 mmole) [prepared as described in Example66 (g) of U.S. Pat. No. 5,552,397] was dissolved in methanol (9 ml) in a100-ml flask equipped with an addition funnel, internal temperatureprobe and argon inlet. To the solution was added DL-dithiothreitol (34mg, 0.22 mmole). The solution was sparged with argon for 15 minutes andthen kept under argon. The resulting solution was cooled to 0° C. in anice-bath. In the addition funnel, 1N sodium hydroxide (26.8 ml, 26.8mmole) was sparged with argon for 30 minutes. The sparged sodiumhydroxide solution was added to the reaction flask over 30 minutes sothat the internal temperature did not exceed 5° C. The reaction wasallowed to stir at 0° C. for 30 minutes and then the ice-bath wasremoved to allow the reaction to warm to room temperature over one hour.The reaction was stirred at room temperature for an additional 1.5 hoursat which time TLC showed that the reaction was complete. A pH probe wasattached to the reaction flask. The reaction was acidified withpreviously sparged 3N HCl to a pH of 6. A few seed crytals were addedand the mixture was stirred for 5 minutes. The mixture was then furtheracidified to pH 2. The resulting slurry was stirred at room temperaturefor one hour. The product was collected by filtration and washed withdistilled water until the wash-water tested negative for chloride withsilver nitrate solution. The product was air-dried for 30 minutes,washed with t-butyl methyl ether (2×4 ml) and hexane (2×4 ml),air-dried, and dried under a high vacuum to give 1.5 g of title productas a white crystalline solid (89% yield), m.p. 176° -177°;[α]_(D)=−18.1° (c =1.0, chloroform). TLC:R_(f)=0.51 (silica gel, 2%acetic acid/ethyl acette; visualized by UV light and cericsulphate/ammonium molybdate).

[0072] Anal. calc'd for C₁₉H₂₆N₂O₄S.2.6 H₂O: C, 60.30; H, 6.92; N, 7.40;S, 8.47. Found: C, 60.02; H, 6.81; N, 7.34; S, 8.60.

EXAMPLE 3 [4S-[4α(R*),7α10aβ]]-Octahydro-4-[(2-mercapto-1-oxo-3-phenylpropl)amino]-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylicacid, methyl ester

[0073] [4S-[4α(R*),7α10aβ]]-Octahydro-4-[(2(acetylthio)-1-oxo-3-phenylpropyl]amino]-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylicacid, methyl ester (700 g, 1.51 moles) was dissolved in methanol (7.7 1)in a 10 l flask equipped with an internal temperature probe and argoninlet. To the solution was added D,L-dithiothreitol (24.6 g, 0.16moles). The solution was thoroughly purged with argon for 30 minutes.The solution was cooled to −15° C. and finely ground potassium carbonate(311.6 g, 2.25 moles) was added with agitation. After completion of thereaction (no starting material was detected by either TLC or HPLC), thepotassium carbonate was removed by filtration. The filter cake waswashed with methanol (400 ml). The temperature of the filtrate was keptat 0° C. while it was transferred to another 10 1 flask. ConcentratedHCl (280 ml) which had been purged with argon was added rapidly withagitation. The desired product crystallized immediately and theresulting suspension was agitated at 10° C. for 30 minutes. Ice water(3.5 1) was added and the suspension was agitated at 0° C. for one hour.The crystals were collected by filtration. The product was washed with1.8 1 of methanol/water (2:1) at 0° C. followed by 1 l of cold water andfinally washed twice with 1 l portions of methyl-tert-butyl ether anddried to give 594 g (93.5w) of title compound as a solid.

EXAMPLE 4 [4S-[4α(R*),7α10aβ]]-Octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl) amino=9-5-oxo-7H-pyrido [2,1-b][1,3]thiazepine-7-carboxylic acid, methyl ester

[0074] A slurry of [4S-[4α(R*),7α,10aβ]]-4-aminooctahydro-5-oxo-7H-pyrido[2,1-b][1,3]thiaze-pine-7-carboxylicacid, methyl ester, hydroiodide (150 g, 0.388 mol) andα-(acetylthio)benzenepropanoic acid, dicyclohexylamine salt (181.2 g,0.447 mol) in methylene chloride (525 ml) was cooled to about −20° C.and treated with a slurry of N-ethyl—N′-dimethylamino-propylcarbodiimide(100.5 g, 0.524 mol) in methylene chloride (500 ml) while maintainingthe pot temperature at less than −5° C. Additional methylene chloride(175 ml) was used to complete the transfer of the carbodiimide. Thereaction was stirred at −5° to −12° C. until complete as determined byHPLC (about 18 hours). The cold reaction was filtered into dilutephosphoric acid (450 ml, 1:3 v/v of 85% phosphoric acid to water) andthe filter cake was washed with methylene chloride (3×100 ml). Thephases of the filtrate were separated and methyl tert-butyl ether (1000ml) was added to the organic layer. The solvents were removed undervacuum to a pot volume of about 900 ml, and the slurry was filtered. Thefilter cake was washed with methyl tert-butyl ether (3×55 ml) and thefiltrate was diluted with additional methyl tert-butyl ether (750 ml).The organic phase was washed with dilute phosphoric acid (450 ml, 1:3v/v of 85% phosphoric acid to water), aqueous sodium bisulfite (3% w/v,450 ml), and 5% aqueous sodium chloride (450 ml). The organic solutionwas filtered to remove any insoluble material and treated withD,L-dithiothreitol (6 g). Degassed methanol (2000 ml) was added and thesolvents were distilled at about 20 mm of mercury until the pot volumewas about 2200 ml. The solution of [4S-[4α(R*),7α,10aβ]]-octahydro-4-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylicacid, methyl ester was cooled to 0° to 5° and treated with 40% aqueousmethylamine (150 ml) while maintaining the pot temperature at less than5° C. The reaction was stirred for about 30 minutes and the pH wasadjusted to 7.5-8.3 using concentrated HCl (155 ml) containingD,L-dithiothreitol (2% w/v). The resulting slurry was stirred for 30minutes at 5° C., the pH was readjusted to 7.5-8.3, if necessary, andthe product was filtered and washed with cold, degassed 3:1methanol/water (3×300 ml). Drying in vacuo afforded 134.1 g of the titleproduct.

[0075] The above procedure was also carried out with the followingmodifications. A sodium bicarbonate wash was utilized before thetreatment with D,L-dithiothreitol, acetonitrile was employed in place ofmethanol after the treatment with D,L-dithiothreitol, and the pH wasadjusted employing D,L-dithiothreitol in acetic acid rather thanconcentrated HCl.

EXAMPLE [S-(R*,R*)]-Hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid

[0076] a)[S-(R*,R*)]-6-[[2-(Acetylthio-1-oxo-3-phenylpropyl]amino]hexahydro-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid, 1,1-dimethyl-ethyl ester

[0077] A solution of(S)-6-aminohexahydro-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid,1,1-dimethylethyl ester (0.781 g, 2.8 mmole) in methylene chloride(11 ml) was cooled in an ice-bath and powdered(S)-2-(acetylthio)benzenepropanoic acid (0.641, 2.86 mmole) was added. Aclear solution was obtained in a minute.1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.642 g,3.351 mole) was added and the mixture was stirred for 2.5 hours. Thesolvent was evaporated and the residue was taken up in ethyl acetate (25ml) and 1N HCl (15 ml). The aqueous layer was separated and extractedwith ethyl acetate (25 ml). The combined organic extracts were washedsuccessively with 1N HCl (2×15 ml), brine, saturated aqueous sodiumbicarbonate (2×10 ml) and brine (10 ml). The solution was dried oversodium sulfate and evaporated to give 1.32 g (93% yield) of titleproduct as a white foam. [α]_(D)=−48.90° (c=1, ethyl acetate).

[0078] Anal. calcl'd for C₂₅H₃₆N₂O₅S.0.4H₂O: C, 62.06; H, 7.67; N, 5.79,S, 6.63. Found: C, 62.28; H, 7.63; N, 5.75, S, 6.44.

[0079] b)[S-(R*,R*)]-6-[[2-(Acetylthio)-1-oxo-3-phenylpropyl]amino]hexahydro-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid

[0080] Trifluoroacetic acid (9.0 ml, 126 mmole) was added to a solutionof the product from part (a) (3.75 g, 7.88 mmole) in methylene chloride(30 ml). After 5 hours, dibasic sodium phosphate (8.4 g, 59.1 mmole)dissolved in water (50 ml) was added to the reaction mixture chilled inan ice bath. The pH of the mixture dropped to 1.4 and was adjusted to2.9 with 10N sodium hydroxide. The layers were separated and the organiclayer was washed with a solution of dibasic sodium phosphate (0.5 g) inwater (25 ml) after adjusting its pH to 2.9 with concentrated HCl. Thelayers were backwashed with methylene chloride (5 ml). The combinedorganic layers were dried over sodium sulfate and evaporated. Theresidue was dissolved in methylene chloride (6 ml) and heptane (24 ml)was added slowly with stirring over 20 minutes. The resulting mass ofcrystals were stirred overnight, filtered, washed with methylenechloride/heptane (1:9), and heptane, and dried under vacuum to give 3.08(93% yield) of title product as colorless crystals; m.p. 160-161° C.;[α]_(D)=−46.6° (c=0.7, chloroform).

[0081] Anal. calcl'd for C₂₁H₂₈N₂O₅S.0.023H₂O: C, 59.47; H, 6.67; N,6.59; S, 7.54. Found C, 59.29; H, 6.61; N, 6.55; S, 7.56.

[0082] c)[S-(R*,R*)]-Hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid

[0083] In a 100 ml flask equipped with an addition funnel, internaltemperature probe, and argon inlet, the title product from part (b) (2.0 g, 4.76 mmole) and D,L-dithiothreitol (0.037 g, 0.24 mmole) werestirred in methanol (6.4 ml). The suspension was sparged with argon for10 minutes, cooled to 1° C., and then kept under argon. In the additionfunnel, 1N sodium hydroxide (19 ml, 19 mmole) was sparged with argon for15 minutes. The sparged sodium hydroxide solution was added to thereaction flask over 20 minutes so that the internal temperature did notexceed 5° C. The reaction was stirred at 10° C. for 30 minutes, and thenthe ice bath was removed to allow the reaction to warm to roomtemperature over 1 hour. A pH probe and a reflux condenser were attachedto the reaction flask. The reaction was acidified with previouslysparged 3N HCl solution to pH 6. The reaction was warmed to 40° C.(internal temperature probe). A few seed crystals of the desired productwere added, and the mixture was further acidified with 3N HCl withstirring to pH 2. The resulting slurry was stirred at 40° C. for 30minutes and then allowed to cool to room temperature over 1 hour.

[0084] The product was collected by filtration and washed with distilledwater (about 30 ml) until the wash-water tested negative for chloridewith silver nitrate solution. The product was air dried for 30 minutes,washed with tert-butyl methyl ether (2×4 ml) and hexane (2×4 ml),air-dried, and dried under high vacuum overnight to give 1.67 (93%) oftitle product as a white solid having the same analytical values as inExample 2.

EXAMPLE 6 [4S-[4α(R*),7α10aβ]]-Octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylicacid

[0085] D,L-Dithiothreitol (10.4 g) was dissolved in methanol (3250 ml)and purged with inert gas to remove oxygen. The solution was cooled to0-5° C. and the methyl ester product from Example 4 (296 g) was added.While stirring, 3N sodium hydroxide (1400 ml) was added at a rate sothat the temperature was maintained at 0-5° C. After stirring for anadditional 30 minutes, the reaction was warmed to room temperature. Whenthe reaction was complete, the pH was adjusted to 1.6-2.0 by theaddition of 3N HCl (1500 ml) resulting in crystallization of theproduct. During addition of the HCl the temperature rose to 30-35° C.Water (2800 ml) was then added, the slurry was cooled to roomtemperature over about one hour, and stirred for an additional hour. Theproduct was filtered and washed with water (4×500 ml) and t-butyl methylether (4×500 ml). The product was then dried to give 272.4 g of titleproduct having the same analytical values as in Example 1.

EXAMPLE 7 [4S-[4α(R*),7α,10aβ]]-Octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylicacid

[0086] All operations were performed under an argon atmosphere and alltransfers were performed using cannulas to minimize exposure of thesubstrate and product to atomospheric oxygen.

[0087] Degassed 1N hydroxide (376 g, dissolved oxygen level is less thanor equal to 5) was added to a 1 liter four necked flask equipped with amechanical stirrer, pH electrode, thermocouple, and argon inlet,containing the methyl ester product from Example 4 (50g) andD,L-dithiothritol (1.8 g). The reaction solution was stirred at 20°±10°C. until hydrolysis was judged complete (HPLC assay, hydrolysis wascomplete about one hour after the addition of the sodium hydroxide wascompleted). The product solution was polish filtered to remove anyparticles, and the hydrolysis vessel and polish filter were washed withwater (50 g). The filtrates were combined in a 1 liter four necked flaskequipped with a mechanical stirrer, pH electrode, thermocouple and argoninlet. With vigorous agitation, the title compound was crystallized at20°±10° C. by the addition of degassed 1N acetic acid (401 g, dissolvedoxygen level is less than or equal to 5%) to a final pH of 5.5±0.5. Thecrystal slurry was agitated at 20+±10° C. for at least one hour,collected on a filter (inert atmosphere was no longer employed), and thewet-cake was washed with water (3×100 g). The wet-cake was dried invacuo to afford 45.1 g of title product as a white crystalline powderhaving the same analytical values as in Example 1.

EXAMPLE 8 Recrystallization Of [4S-[4α(R*),7α,10aβ]]-Octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl)amino]5-oxo-7H-pyrido[2,1-b][2,3]thiazepine-7-carboxylicacid

[0088] All operations were performed under an argon atmosphere and alltransfers were performed using cannulas to minimize exposure of theproduct to atmospheric oxygen.

[0089] Degassed alcohol solution (302 g of absolute ethanol and 87 g ofmethanol, containing less than or equal to 5% oxygen) was added to a 1liter flask equipped with a mechanical stirrer, reflux condenser,thermocouple, and an argon inlet, containing [4S -[4α(R*),7α,10aβ]]-octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylicacid (11 g) and D,L-dithiothreitol (1.1 g). The resulting slurry washeated at reflux (about 75° C.) for about 2 hours to dissolve thesolids. After cooling the solution to about 60° C., it was polishfiltered into a 1 liter four neck flask equipped with a mechanicalstirrer, reflux condenser, thermocouple, and argon inlet. Thedissolution vessel and polish filter were washed with methanol (5 g).With stirring, the combined filtrates were cooled to 20°±10° C., andheld at that temperature for at least one hour. The product wascollected on a filter (inert atmosphere no longer required) and thewet-cake was washed with methanol (3×15 g). The wet-cake was dried invacuo to afford 8.74 g of title product as a white crystalline powder.

EXAMPLE 9 Reprocessing Of[S-(R*,R*)]-Hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid

[0090][S-(R*,R*)]-Hexahydro-6-[(2-mercapto-1-oxo-3-phenyl-propyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid (5 g, 13.2 mmole, HPLC 99.6 area percent), and D,L-dithiothreitol(180 mg, 1.67 mmol) were charged to a three necked flask. The flask wasflushed with nitrogen and immersed in an ice bath. Cold (2° C.)deoxgenated sodium hydroxide solution (1.22 N, 40 ml) were added slowlywhile maintaining the reaction temperature below 10° C. After completeaddition, cooling was removed and the resulting solution was allowed towarm to room temperature. The solution was heated to about 45° C. anddeoxygenated acetic acid solution (1.06N, 50 ml) was added whilemaintaining the temperature of the mixture at about 45° C. The crystalslurry was stirred at about 45° C. for 30 minutes and then allowed tocool to room temperature. After stirring at room temperature for 30minutes, the product was filtered, washed with water (50 ml) and driedin a vacuum oven at 51° C./4.1 inch Hg to afford 4.65 g of titlecompound having a laboratory HPLC of 99.9 area percent.

EXAMPLE 10[S-(R*,R*)]-Hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1aceticacid

[0091] A three necked flask was charged with[S-(R*,R*)]-6-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]hexahydro-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid (10 g, 23.78 mmoles) and D,L-dithiothreitol (390 mg, 2.5 mmoles).The flask was flushed with nitrogen. Deoxygenated water (20 ml) wasadded to the flask and the mixture was cooled to 1° C. Cold (1° C.)deoxygenated sodium hydroxide solution (1.22 N. total 70 ml, 84 mmoles)was added slowly while maintaining the temperature of the reactionmixture between 1° C. and 4° C. After addition of the initial 10 v/v %of the sodium hydroxide solution, the remainder of the solution wasadded, maintaining the reaction temperature between −2° to 3° C. Afterstirring the reaction mixture at −2° to 6° C. for 30 minutes, thereaction mixture was allowed to warm to room temperature. The reactionmixture was polish filtered into a crystallization flask and heated to45° C. Deoxygenated acetic acid solution (1.06 N, 90 ml, 95 mmoles) wasadded while maintaining the reaction temperature between 41° and 46° C.The crystal slurry was stirred at 41° to 46° C. for 20 minutes and thenallowed to cool to room temperature. After stirring at room temperaturefor 30 minutes, the product was filtered and washed with water (100 ml)and dried in a vacuum oven at 51° C./4.1 inch Hg to afford 8.45 g oftitle product having laboratory HPLC of 99.75 area percent.

EXAMPLE 11[S-(R*,R*)]-Hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid

[0092] a)[S-(R*,R*)]-Hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid, ethyl ester

[0093] Under an inert atmosphere, a methylene chloride solution (25 ml)of (S)-2-(acetylthio)benzenepropanoic acid (4.8 g) was cooled to −11° C.and (chloromethylene)dimethyl-ammonium chloride (3.9 g) was added. Thereaction mixture was stirred between −14 and −5° C. for 2 hours. To aseparate reaction vessel, the camphorsulfonic acid salt of(S)-6-aminohexahydro-2,2-dimethyl-7-oxo-1H-azepinine-1-acetic acid,ethyl ester (10 g), potassium bicarbonate (12 g), methylene chloride (25ml), and water (50 ml) were charged. After 10 minutes of stirring abiphasic solution was obtained and cooled to 0° C. With vigorousstirring, the methylene chloride solution of(S)-2-(acetylthio)benzenepropanoyl chloride was added to the biphasicreaction mixture maintaining the pH in the range of 6.8 to 8.5 and thetemperature between 0 to 4° C. Once the reaction was judged complete byin-process HPLC assay, the phases were separated and the product richorganic phase was concentrated to an oily residue under reducedpressure. The oily residue was dissolved in isopropanol (50 ml),concentrated to a residue again and the resulting residue was dissolvedin isopropanol (40 ml). The resulting solution was cooled to 0° C. anddeoxygenated by sparging with nitrogen for at least 15 minutes.D,L-Dithiothreitol (220 mg) and ethanolamine (4 ml) were charged and thereaction mixture was stirred at 0° C. until it was judged complete byHPLC analysis. The pH of the reaction mixture (at 10° C.) was adjustedto 8.56 using a deoxygenated 1 N acetic acid solution (40 ml) to afforda crystal slurry. The pH of the crystal slurry was further adjusted to7.36 using glacial acetic acid (6 drops). After cooling further, thecrystal slurry was stirred at 0° C. for 30 minutes, filtered, and thewet cake was washed with cold (3° C.) aqueous isopropanol (1:1, 44 ml).Initially, the product was suction dried for 1.5 hour under a nitrogenatmosphere and finally dried in a vacuum oven at 41° C. C to afford 7.51g (87.6 M %) of the title compound.

[0094] b)[S-(R*,R*)]-Hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid

[0095] The product from part (a) (5 g), D,L-dithiothreitol (130 mg) anddeoxygenated water (18 ml) were charged to a reaction vessel. Under aninert atmosphere, the mixture was stirred at ambient temperature and asolution of sodium hydroxide (17.5 ml, approximately 2.2 N) was chargedwhile maintaining the temperature between 21 and 25° C. A clear solutionwas observed for 5 minutes after the sodium hydroxide had been added andthe reaction mixture was stirred until the reaction was judged completeby HPLC assay. The solution was heated to 45° C. and deoxygenated aceticacid (43 ml, approximately 1 N) was added to adjust the pH of theproduct slurry to 5.9. The product slurry was stirred at 45° C. for 30minutes, cooled to ambient temperature, filtered and washed with water(50 ml). The wet cake was dried in a vacuum oven at 61° C. to afford 4.2g (90.3 M %) of the title compound.

EXAMPLE 12 Recrystallization Of [4S-[4α(R*),7α,10aβ]]-Octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylicacid

[0096] A flask containing [4S-[4α(R*),7α,10aβ]]-octahydro-4-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-5-oxo-7H-pyrido[2,1-b][1,3]thiazepine-7-carboxylicacid (50.42 g, 123.42 mmol) and D,L-dithiothreitol (1.915 g, 12.41mmole) was deoxygenated and treated with a deoxygenated solution ofsodium hydroxide (0.5 N, 1.3 equiv.). The product dissolves in 3 to 5minutes to give a solution with pH 8-8.5. The resulting colorless topale pink solution was filtered under nitrogen into a crystallizer, andthe dissolution flask and filter were rinsed with deoxygenated water.The product was crystallized by the addition of deoxygenated aqueousacetic acid (1.5 equivalents) which was prepared by dissolving glacialacetic acid (11.11 g, 10.59 ml, 186.8 mmol) in deionized water (175.7ml) and was then deoxygenated by being bubbled with nitrogen. The aceticacid solution was added over 10-15 minutes and the pH fell from 8.1 to7.2. After initial crystallization, additional deoxygenated 1N aceticacid was added over 10 to 15 minutes to complete the crystallization.The final pH of the slurry was 5.3. The product slurry was stirred for 1hour at 15-25° C., filtered, and washed with water and tert-butyl methylether. The desired product was dried under vacuum at 35-45° C. for 16hours to give 49.39 g of product (98% weight yield) having a purity ofgreater than 99%.

What is claimed is:
 1. A deprotection process for converting theacylmercaptoalkanoylamino lactam acid or ester of the formula (II)

to the mercaptoalkanoylamino lactam acid or ester of the formula (I)

or for converting the mercaptoalkanoylamino lactam ester of formula I tothe corresponding lactam acid of formula I wherein: X₁ is a lactam ofthe formula (IV)

R₄ and R₅ are both hydrogen; R₆ and R₇ are both methyl; R₁₀ an R₁₁ areboth hydrogen; b is zero; q is two; m is zero or an integer from 1 to 6;n is zero or one; R₁ and R₂ are independently selected from straight orbranched chain alkyl of 1 to 6 carbons, —(CH₂)_(m)-aryl,—(CH₂)_(m)-substituted aryl, or —(CH₂)_(m)-heteroaryl; and R₁₂ ishydrogen or an acid protecting group selected from methyl, ethyl,propyl, phenyl or benzyl; which comprises a) when R₁₂ in the definitionof X₁ in formula II is hydrogen, treating the acylmercaptoalkanoylaminolactam acid of formula II with an alkali metal or alkaline earth metalhydroxide or carbonate or with an amine in a suitable solvent containinga sufficient amount of an agent that minimizes the amount of thedisulfides of the formula (III)

which, in turn, minimizes the formation of the undesired epimer of thepharmaceutically active compounds of formula I followed by treatmentwith an aqueous acid to precipitate the desired lactam acid of formulaI; or b) when R₁₂ in the definition of X₁ in formula II is an acidprotecting group, treating the acylmercaptoalkanoylamino lactam ester offormula II under aqueous conditions with an alkali metal or alkalineearth metal hydroxide or carbonate in a suitable solvent containing asufficient amount of an agent that minimizes the amount of thedisulfides of formula III which, in turn, minimizes the formation of theundesired epimer of the pharmaceutically active compound of formula Ifollowed by treatment with an aqueous acid to precipitate the desiredlactam acid of formula I; or c) when R₁₂ in the definition of X₁ informula II is an acid protecting group, treating theacylmercapto-alkanoylamino lactam ester of formula II under non-aqueousconditions with an alkali metal or alkaline earth metal hydroxide orcarbonate in a suitable solvent containing a sufficient amount of anagent that minimizes the amount of the disulfides of formula III which,in turn, minimizes the formation of the undesired epimer of thepharmaceutically active compound of formula I or treating theacylmercaptoalkanoylamino lactam ester of formula II under aqueousconditions with an amine in a suitable solvent containing a sufficientamount of an agent that minimizes the amount of the disulfides offormula III which, in turn, minimizes the formation of the undesiredepimer of the pharmaceutically active compound of formula I thusremoving the acyl protecting group R₂—C(O)— to give themercaptoalkanoylamino lactam ester of formula I; or d) treating themercaptoalkanoylamino lactam ester of formula I under aqueous conditionswith an alkali metal or alkaline earth metal hydroxide or carbonate in asuitable solvent containing a sufficient amount of an agent thatminimizes the amount of the disulfides of formula III, which, in turn,minimizes the formation of the undesired epimer of the pharmaceuticallyactive compound of formula I followed by treatment with an aqueous acidto precipitate the desired mercaptoalkanoylamino lactam acid of formulaI.
 2. The process of claim 1 wherein the agent that minimizes the amountof the disulfide of formula III is a bismercaptan of the formula

wherein k is an integer from 1 to 4 and each X₂ is independentlyselected from hydrogen and hydroxy, or the bismercaptan is1,2-benzenedimethanethiol, 1,3-butanedithiol meso-α,α′-dimercaptoadipicacid, disodium salt, or durene-α(1),α(2)-dithiol, or the agent is aphosphine or phosphite reducing agent, or the agent is zinc metalpowder, or the agent is sodium hydrosulfite.
 3. The process of claim 2wherein the bismercaptan is dithiothreitol or dithioerythritol, thephosphine reducing agent is tributyl phospine or triphenyl phosphine,and the phosphite reducing agent is triethyl phosphite.
 4. The processof claim 3 wherein: R₁₂ in the acylmercaptoalkanoylamino lactam offormula II is hydrogen, methyl, ethyl, propyl, phenyl or benzyl and R₁₂in the mercaptoalkanoylamino lactam of formula I is hydrogen; n is zero;R₁ is benzyl; and the agent that minimizes the amount of the disulfideof formula III and, in turn, minimizes the formation of the undesiredepimer of the pharmaceutically active compound of formula I is thebismercaptan dithiothreitol or dithioerythritol.
 5. The process of claim4 wherein: a) the acylmercaptoalkanoylamino lactam acid of formula II is[S-(R*,R*)]-hexahydro-6-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid which is dissolved in methanol and treated with D,L-dithiothreitoland sodium hydroxide; and b) following completion, the above reactionmixture is treated with aqueous hydrochloric acid to precipitate[S-(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid.
 6. The process of claim 4 wherein: a) theacylmercaptoalkanoylamino lactam ester of formula II is[S-(R*,R*)]-hexahydro-6-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid, ethyl ester which is dissolved in methanol and treated withD,L-dithiothreitol and sodium hydroxide under aqueous conditions; and b)following completion, the above reaction is treated with aqueoushydrochloric acid to precipitate[S-(R*,R*)]-hexahydro-6-[2-(mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid.
 7. The process of claim 4 wherein: a) theacylmercaptoalkanoylamino lactam acid of formula II is[S-(R*,R*)]-hexahydro-6-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid which is slurried in water and treated with D,L-dithiothreitol andsodium hydroxide; and b) following completion, the above reactionmixture is treated with aqueous acetic acid to precipitate[S-(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenyl-propyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid.
 8. The process of claim 4 wherein: a) the acylmercaptoalkanoyllactam ester of formula II is[S-(R*,R*)]-hexahydro-6-[[2-(acetylthio)-1-oxo-3-phenylpropyl]amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid, ethyl ester which is dissolved in isopropanol and treated withD,L-dithiothreitol and ethanolamine under aqueous conditions to give[S-(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid, ethyl ester; and b) the product from part (a) is slurried in waterand treated with D,L-dithiotreitol and sodium hydroxide and followingcompletion, the above reaction mixture is treated with aqueous aceticacid to precipitate[S-(R*,R*)]-hexahydro-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-aceticacid.